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This study examined the effect of rare PDE5A variants on coronary artery disease risk from several genetic and pharmacological aspects. Our study provides evidence of a putative causal effect of PDE5A overexpression on coronary artery disease and myocardial infarction. Furthermore, these findings vigorously promote PDE5 inhibition as a promising strategy to encounter coronary artery disease. However, this remains to be studied. Im Rahmen dieser Studie wurde genetisch und pharmakologisch untersucht, wie sich das Tragen seltener PDE5A Varianten auf das Risiko für koronare Herzerkrankungen auswirkt. In diesem Zusammenhang konnten wir einen mutmaßlich kausalen Zusammenhang zwischen einer PDE5A Überexpression und einem erhöhtem Risiko für koronare Herzerkrankungen feststellen. Diese Erkenntnisse erwecken den Eindruck, dass die Anwendung eines PDE5-Hemmers bei koronaren Herzerkrankungen von großem Nutzen sein könnte, was jedoch weiterer Untersuchungen bedarf.

This work presents the preparation of bioactive glasses 70SiO2–(26 − x)CaO–4P2O5–xAg2O (with x = 0, 1, 3, 10 mol%) by a modified sol–gel method with reduced synthesis time based on hydrothermal reaction in a medium without acid or base catalysts.

Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr−/− mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. Importantly, pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr−/− mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD.

Recent trials of glucose-lowering drugs (GLDs) have drawn attention to renal outcomes. Our goal was to understand how patients with diabetic kidney disease (DKD) are treated in general practices in the United States.Retrospective cohort study using a national-level claims data set and electronic health records.Patients (≥ 18 years) with type 2 diabetes, whose estimated glomerular filtration rates (eGFRs) were between 15 and 89 mL/min/1.73 m2 between 2016 and 2018, were selected. Use of different GLDs during a 12-month period was examined across all eGFR levels.Of the 25,486 sample patients, 69.2%, 18.9%, 9.6%, and 2.3% had an eGFR in the ranges of 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m2, respectively. Metformin was used by nearly 33% of patients with an eGFR of 30 to 44 mL/min/1.73 m2 and by 10% of patients with an eGFR less than 30 mL/min/1.73 m2. Less than 10% (across all eGFR levels) of patients used glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. Use of insulin was more frequent among patients with a lower eGFR (P .05). The findings were similar in subgroups with different hemoglobin A1c levels ( 7% and ≥ 7%).Real-world treatment of DKD in the United States is suboptimal. Inappropriate use of some GLD classes, especially in advanced DKD stages, was found along with lower than expected use of modern agents that are considered safe and effective to treat glycemic outcomes. Efforts may be needed to improve understanding of safety, glycemic efficacy, and overall clinical value of GLDs across DKD stages.

Objective Weight reduction is a key component of diabetes management in adults with type 2 diabetes mellitus (T2DM), yet the benefits of weight loss in T2DM patients have been difficult to quantify. We examined the medical literature regarding the relationships between weight change and 1) glycemic control and 2) cost and resource use. Methods Systematic searches were conducted in the electronic databases Embase, MEDLINE, and the Cochrane Database of Systematic Reviews to identify publications regarding the impact of weight change on T2DM outcomes from 2007 onward. Identified publications were screened for relevance against predefined eligibility criteria, and methodological approaches and results were extracted. Evidence for the impact of weight change on outcomes was evaluated and used to identify strengths, limitations, and gaps in the current literature. Results The number of studies meeting eligibility criteria for each outcome was: glycemic control (n=38) and cost and resource use (n=11). The relationship between weight change and glycemic control was dependent on the interplay of multiple factors, eg, the weight loss interventions employed, the antidiabetic medication classes used, the time horizon, and baseline BMI and glycemic control. With respect to cost and resource use, the review indicated that savings were associated with weight loss, and increased costs were associated with weight gain. Conclusion Studies regarding weight change in T2DM patients demonstrated varying effects on glycemic control and a positive association with costs and resource use, where weight loss was associated with decreased costs and resource use. Future studies may be able to clarify these relationships.

The ferromagnetic Fe3O4 nanoparticles with the average particle size of about 10 nm were used to adsorb chromium (VI) in aqueous solution. The equilibrium of Cr(VI) adsorption can be achieved at the pH value of 2.5, in the contact time of 120 minutes. The mechanisms of Cr(VI) adsorption were evaluated by 4 isothermal adsorption models Langmuir, Freundlich, Redlich-Peterson, and Temkin. The results showed that all four models are satisfied; especially, Redlich-Peterson is the most suitable model to describe the adsorption kinetic of Cr(VI) on ferromagnetic Fe3O4 nanoparticles.

There have been a number of studies on the effects of formative assessment on Learning Management System on EFL writing achievement. Nevertheless, in the context of Vietnam, little research has been done on education technology that enhances online formative assessment in teaching writing. In an attempt to further the previous research nationwide and worldwide, this study examined the impacts of formative assessment on students’ writing achievement in a writing course of Learning Management System Schoology. A quasi-experimental design was carried out among two groups of fifty undergraduate Vietnamese students over a fifteen-week writing course using the main activity named online discussion board. The data analysis from the writing test scores suggested that there was statistically significant difference between treatment group and control group of participants. It is recommended that teachers should employ online formative assessment in teaching writing to help improve writing achievement among EFL learners in Vietnam and similar contexts.

Aims: The efficacy and safety of oral semaglutide, the first glucagon-like peptide-1 (GLP-1) receptor agonist developed for oral administration for the treatment of type 2 diabetes, was evaluated i...

Introduction Therapeutic inertia refers to the failure to initiate or intensify treatment in a timely manner and is widespread in type 2 diabetes (T2D) despite the well-established importance of maintaining good glycemic control. The aim of this analysis was to quantify the clinical and economic burden associated with poor glycemic control due to therapeutic inertia in patients with T2D in the USA. Methods The IQVIA CORE Diabetes Model was used to simulate life expectancy, costs associated with diabetes-related complications, and lost workplace productivity in US patients. Baseline glycated hemoglobin (HbA1c) levels were 7.0% (53 mmol/mol), 9.0% (75 mmol/mol), 11.0% (97 mmol/mol) 13.0% (119 mmol/mol), or 15.0% (140 mmol/mol), with targets of 6.5% (48 mmol/mol), 7.0% (53 mmol/mol), 8.0% (64 mmol/mol), or 9.0% (75 mmol/mol) depending on baseline HbA1c, across several delayed intensification scenarios (values above target were defined as poor control). The burden associated with intensification delays of 1, 2, 3, 5, and 7 years was estimated over time horizons of 1–30 years. Future costs and clinical benefits were discounted at 3% annually. Results In a population of 13.4 million patients with T2D and baseline HbA1c of 9.0% (75 mmol/mol), delaying intensification of therapy by 1 year was associated with a loss of approximately 13,390 life-years and increased total costs of US dollars (USD) 7.3 billion (1-year time horizon). Longer delays in intensification were associated with a greater economic burden. Delaying intensification by 7 years was projected to cost approximately 3 million life-years and USD 223 billion over a 30-year time horizon. Conclusion Therapeutic inertia is common in routine clinical practice and makes a substantial contribution to the burden associated with type 2 diabetes in the USA. Initiatives and interventions aimed at preventing therapeutic inertia are needed to improve clinical outcomes and avoid excess costs. Electronic Supplementary Material The online version of this article (10.1007/s12325-019-01199-8) contains supplementary material, which is available to authorized users.

International audience; Abstract Disease progression and therapeutic resistance of prostate cancer (PC) are linked to multiple molecular events that promote survival and plasticity. We previously showed that heat shock protein 27 (HSP27) acted as a driver of castration-resistant phenotype (CRPC) and developed an oligonucleotides antisense (ASO) against HSP27 with evidence of anti-cancer activity in men with CRPC. Here, we show that the tumor suppressor Menin ( MEN1 ) is highly regulated by HSP27. Menin is overexpressed in high-grade PC and CRPC. High MEN1 mRNA expression is associated with decreased biochemical relapse-free and overall survival. Silencing Menin with ASO technology inhibits CRPC cell proliferation, tumor growth, and restores chemotherapeutic sensitivity. ChIP-seq analysis revealed differential DNA binding sites of Menin in various prostatic cells, suggesting a switch from tumor suppressor to oncogenic functions in CRPC. These data support the evaluation of ASO against Menin for CRPC.

Introduction Liraglutide and sitagliptin were compared on glycemic control and all-cause healthcare costs over a 1-year period among older adults with type 2 diabetes (65–89 years) enrolled in a national Medicare Advantage Prescription Drug health plan. Methods This was a retrospective study in which the index date was the first prescription fill for liraglutide or sitagliptin between 25 January 2010 and 31 December 2014. Post-index treatment persistence and glycosylated hemoglobin (HbA1c) at baseline and 1 year (± 90 days) post-index date were required. Patients were excluded if their record included use of insulin during the baseline period. Inverse probability of treatment weighting using stabilized weights was employed with final covariate adjusted regression modeling to estimate the primary outcome (mean change in HbA1c) and secondary outcomes (achieving glycemic goal and costs), each at 1-year post-index date. Results Overall, 3056 patients met the selection criteria, of whom 218 filled prescriptions for liraglutide and 2838 for sitagliptin. Adjusted mean change in HbA1c at 1 year post-index was − 0.42 with liraglutide versus − 0.12 with sitagliptin (P = 0.0012). Adjusted odds of achieving the treatment goals of HbA1c

The tumor suppressor menin has dual functions, acting either as a tumor suppressor or as an oncogene/oncoprotein, depending on the oncological context. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2) and is often a basal-like breast cancer. TNBC is associated with a dismal prognosis and an insufficient response to chemotherapies. Previously, menin was shown to play a proliferative role in ER-positive breast cancer, however, the functions of menin in TNBC remain unknown. Here, we have demonstrated that menin is expressed in various TNBC subtypes with the strongest expression in the TNBC Hs 578T cells. The depletion of menin by an antisense oligonucleotide (ASO) inhibits cell proliferation, enhances apoptosis in Hs 578T cells, highlighting the oncogenic functions of menin in this TNBC model. ASO-based menin silencing also delays the tumor progression of TNBC xenografts. Analysis of the menin interactome suggests that menin could drive TNBC tumorigenesis through the regulation of MLL/KMT2A-driven transcriptional activity, mRNA 3′-end processing and apoptosis. The study provides a rationale behind the use of ASO-based therapy, targeting menin in monotherapy or in combination with chemo or PARP inhibitors for menin-positive TNBC treatments.

Helicobacter pylori (Hp) has been strongly implicated as a causative factor in peptic ulcer disease, and in significantly increasing the risk of developing gastric cancer. Commercial vaccines nowadays have shown less efficiency on preventing the disease caused by Hp. Therefore, this study was performed to clone nap gene from Hp and over-express the encoded protein (NAP) in E. coli cells. NAP (Neutrophil-activating protein) has been considered as a potential antigen of Hp, can be used to produce peptic ulcer prevention vaccine. The obtained results showed that E. coli OmniMAX and E. coli BL21 (DE3) strains carrying recombinant plasmid pET11a-nap were cloned successfully and remained stable in medium supplemented with ampicillin. Over-expression of NAP protein fused with 6xHis in E. coli was demonstrated via SDS-PAGE and Western blot. The result revealed that the highest target protein production level (29.73%) was obtained in the medium added 0.5 mM IPTG at 37 oC after 6 hours of induction. This is the preliminary research for over-production and purification of Hp-NAP protein that may be used in further applications.

Introduction Orally administered semaglutide is the first glucagon-like peptide 1 receptor agonist (GLP-1 RA) for oral administration. As head-to-head trials assessing orally administered semaglutide as an add-on to 1–2 oral antidiabetic drugs (OADs) vs other GLP-1 RAs are limited, a network meta-analysis (NMA) was performed to assess the relative efficacy and safety of orally administered semaglutide 14 mg once-daily (QD) vs injectable GLP-1 RAs in patients with type 2 diabetes inadequately controlled on 1–2 OADs. Methods A systematic literature review was conducted to identify randomised controlled trials of GLP-1 RAs in patients inadequately controlled on 1–2 OADs. Data at 26 ± 4 weeks were extracted for efficacy and safety outcomes feasible for the NMA: change from baseline in glycated haemoglobin (HbA1c), weight, HbA1c target levels (